Safety and Tolerability of Azilsartan Medoxomil Plus Chlorthalidone Compared to Olmesartan Medoxomil Plus Hydrochlorothiazide in Subjects With Essential Hypertension

Official Title: “A Phase 3, Open-Label, Randomized, Long-Term Comparison of the Safety and Tolerability of the TAK-491 Plus Chlorthalidone Fixed-Dose Combination vs. Olmesartan Medoxomil-Hydrochlorothiazide Fixed-Dose Combination in Subjects With Essential Hypertension”

The purpose of this study is to compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone, once daily (QD), versus olmesartan medoxomil-hydrochlorothiazide in subjects with essential hypertension.

High Blood Pressure (Hypertension) is the most common cause of preventable death in developed nations. Uncontrolled hypertension greatly increases the risk of heart disease, brain disease, and kidney failure. As the population ages, the incidence of hypertension will continue to increase if effective preventive measures are not implemented. Despite the availability of antihypertensive agents, hypertension is not adequately controlled; only about one in three patients successfully keep blood pressure normal.

Treatment for high blood pressure includes thiazides or thiazide-like diuretics, either alone or as part of combination treatment. Chlorthalidone is a commercially available, orally administered thiazide-type diuretic agent.

TAK-491 (azilsartan) is an angiotensin II receptor blocker being evaluated by Takeda to treat subjects with high blood pressure (essential hypertension).

This study will compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone (TAK-491CLD) fixed-dose combination to olmesartan medoxomil-hydrochlorothiazide fixed-dose combination.

Initially patients will undergo a Screening Visit to confirm that they are eligible to participate in the study. All participants will receive the study drug for up to 52 weeks.

The dose of the study drug may be gradually increased throughout the study so that a target blood pressure value can be reached for each participant.

Throughout the treatment period of the study, participants will be required to visit the research site for 11 visits. At these study visits participants will be required to undergo certain study procedures including physical examinations, vital sign measurements (blood pressure, heart rate, weight and height), electrocardiograms (monitoring of the heart), and blood and urine samples taken for clinical laboratory tests.

Intervention(s) in this Clinical Trial

• Drug: Azilsartan medoxomil and chlorthalidone
  • Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who do not achieve target blood pressure by Week 4, titration to a maximum dose of azilsartan medoxomil 80 mg and chlorthalidone 25 mg.
• Drug: Olmesartan medoxomil and hydrochlorothiazide
  • Participants in North America: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who do not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg. Participants in Europe: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who do not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Azilsartan Medoxomil and Chlorthalidone QD
• Active Comparator: Olmesartan Medoxomil and Hydrochlorothiazide QD

Primary Measures

• Percentage of subjects with Adverse Events.
  • Time Frame: Up to Week 52
    Safety Issue?: Yes

Secondary Measures

• Percentage of subjects with serum creatinine elevations from baseline greater than 50% and greater than the upper limit of normal.
  • Time Frame: Baseline and Week 52
    Safety Issue?: Yes

Inclusion Criteria:

• Is treated with antihypertensive therapy and has a post-washout mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm
• Hg on Day, or has not received antihypertensive treatment within 14 days prior to Screening and has a mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg at the Screening Visit and on Day 1.
• Females of childbearing potential who are sexually active agree to routinely use adequate contraception, and can neither be pregnant nor lactating from before study participation to Screening to 30 days after the last study drug dose.
• Has clinical laboratory test results within the reference range for the testing laboratory or the investigator does not consider the results to be clinically significant.
• Is willing to discontinue current antihypertensive medications up to 3 weeks before enrollment.

Exclusion Criteria:

• Has a mean clinic diastolic blood pressure (sitting, trough) greater than 119 mm Hg on Day 1.
• Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).
• Has a recent history (within the last 6 months) of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident or transient ischemic attack.
• Has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome).
• Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
• Has severe renal dysfunction or disease.
• Has known or suspected unilateral or bilateral renal artery stenosis.
• Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug.
• Has poorly-controlled type 1 or 2 diabetes mellitus at Screening.
• Has hypokalemia or hyperkalemia at Screening.
• Has an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice at Screening.
• Has any other known serious disease or condition that would compromise safety, might affect life expectancy, or make it difficult to successfully manage and follow according to the protocol.
• Has known hypersensitivity to angiotensin II receptor blockers or thiazide-type diuretics or other sulfonamide-derived compounds.
• Has been randomized/enrolled in a previous azilsartan or azilsartan medoxomil plus chlorthalidone study.
• Currently is participating in another investigational study or has received any investigational compound within 30 days prior to Screening.
• Has a history of drug abuse or a history of alcohol abuse within the past 2 years.
• Is taking or expected to take any excluded medication, including:
• Antihypertensive medications must be discontinued completely by Day -14, except antihypertensive medications used in the open-label treatment period in accordance with the titration-to-target blood pressure titration.
• Angiotensin II receptor blockers or thiazide-type diuretics other than study medication.
• Over-the-counter products not permitted by investigator.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Takeda Global Research & Development Center, Inc. Industry

Overall Clinical Trial Officials and Contacts

Executive Medical Director, Clinical Science Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00996281

Study ID Number: TAK-491CLD_308

ClinicalTrials.gov Identifier: NCT00996281

Health Authority: United States: Food and Drug Administration

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